The deleterious effects of vascular-associated disorders such as stroke, heart attack, and artherosclerosis are thought to be caused, at least in part, by the inappropriate triggering of a vascular inflammation and repair response. The vascular inflammation and repair response involves adhesive interactions between various cell types normally found freely circulating in blood. Examples of such interactions include those that can occur between platelets, leukocytes and the inner wall of blood vessels (i.e., the vascular endothelium). Under conditions of high fluid shear forces, platelets adhere to the endothelium via an interaction between the glycoprotein (GP) Ib-IX-V complex on their surface and von Willebrand factor (vWF) present on exposed vessel subendothelium. In addition, platelets adhering to the vascular endothelium can bind and capture freely circulating platelets via vWF-mediated tethering, enabling thrombus growth through successive layers of platelets. The GPIbα chain of the GPIb-IX-V complex can also facilitate the binding of α-thrombin to the platelet surface, enhancing the thrombin-mediated cleavage of GPV and protease-activated receptors (PARs).
In contrast, leukocytes can adhere to activated endothelium either directly, or indirectly by first adhering to vWF-immobilized platelets. In both instances, leukocyte cell surface molecules that bind to either the selectin or integrin classes of adhesion receptors mediate these adhesion events. Leukocyte-platelet adhesion is thought to occur, in part, via interaction of the leukocyte surface integrin molecule MacI and the GP1b component of the platelet surface GPIb-IX-V complex.
In response to vascular disturbances such as atherosclerotic plaque rupture or mechanical injury, e.g., such as that caused by angioplasty, stent placement, cardiopulmonary bypass procedures, ischemic damage or stenosis, leukocytes and platelets can accumulate at a vascular lesion site and provide multiple adhesive substrates for one another. This accumulation of leukocytes and platelets leads to the local production of factors including, e.g., mitogens, cytokines and chemokines, causing the further undesirable progression of a vascular disease.
Therapeutic polypeptides including a vWF-binding region derived from GPIbα have been described. One such polypeptide is based on a sequence containing two amino acid substitutions (G233V M239V) in the amino acid sequence of wild-type human GPIbα. An Ig fusion protein containing 290 amino acids of the extracellular, vWF-binding domain of this variant (named GPIb2V-Ig) of this variant inhibits coronary artery thrombosis.